PROJECT DESCRIPTION: This SBIR Phase II proposal is intended to further develop human ghrelin (hGhr) and human growth hormone (hGH) as a combination therapy for elderly patients with sepsis and septic shock. In the US, more than one million people develop sepsis every year, and nearly 80% of septic deaths occur in patients older than 65 years of age. Currently, no effective pharmacotherapy exists for the treatment of sepsis. One of the reasons for sepsis clinical trial failures is that the preclinical evaluation of anti-sepsis drug candidates has been conducted exclusively in young animals. Rat Ghr, for example, ameliorates sepsis in young, but not aged, rats. We have discovered that administration of GH upregulates the expression of the Ghr receptor and restores Ghr?s responsiveness in aged animals with sepsis. In our completed SBIR Phase I project, co-administration of hGhr and hGH (hGhr-hGH) significantly ameliorated sepsis-associated lung, liver, and kidney injury in septic aged animals. We further demonstrated that the combination therapy nearly doubled the survival rate of septic aged rats. Moreover, both hGhr and hGH have been clinically tested and used for other indications with an excellent safety profile. Based on our Phase I results, we hypothesize that hGhr-hGH can be further developed as an effective therapy for sepsis in the elderly. To advance hGhr-hGH therapy towards its clinical use against sepsis in the elderly, we plan to determine the combination therapy?s most effective dose and therapeutic window to attenuate tissue injury and improve survival. We will also study hGhr-hGH?s combination effects on safety and pharmacokinetics (PK). Finally, we will conduct an exploratory study in an ovine model of sepsis to evaluate hGhr-hGH?s effects on hemodynamic parameters and organ injury. These proposed studies should provide crucial information for the future filing of an IND application to further develop hGhr-hGH in clinical trials. Our ultimate goal is to obtain FDA approval for the use of hGhr-hGH as a safe and effective treatment for elderly patients with sepsis and septic shock.